Effect of hypoxia-inducible factor-1α induction by CoCl2 on breast cancer cells survival: influence of cytochrome-c and survivin

Reni Paramita, Mohamad Sadikin, Noorwati Sutandyo, Septelia I. Wanandi

DOI: https://doi.org/10.13181/mji.v23i3.933


Background: Tumor tissue usually became hypoxic due to disruption of oxygen supply. Adaptation response to hypoxia is mediated by transcription factor, hypoxia- inducible factor-1α (HIF-1α). HIF-1α signaling is known to increase the expression of pro-apoptotic protein cytochrome-c, and anti- apoptotic survivin. In this study we wanted to analyze the role of HIF-1α on breast cancer cells survival through pro-apoptosis cytohrome-c and anti-apoptosis survivin regulation.

Methods: Breast cancer cell lines T47D were induced by CoCl2 then harvested to analyze the expression of HIF-1α, protein cytochrome-c, mRNA survivin and cell viabilities.

Results: HIF-1α induction by CoCl2 causes the increase of  protein and mRNA of HIF-1α, cytochrome-c protein, and survivin mRNA, but does not cause the changes in cell viability.

Conclusion: HIF-1α induction have no effects on breast cancer cell line T47D viabilities due to the balance regulation between pro-apoptosis expression cytochrome-c and anti-apoptosis survivin.


apoptosis; cell viability; cytochrome-c; hypoxia-inducible factor-1α; survivin

Full Text:



  1. International Agency for Research on Cancer (IARC) [Internet]. Breast Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012. World Health Organization 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
  2. Okazaki T, Ebihara S, Asada M, Yamanda S, Niu K, Arai H. Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival tumor-bearing mice by enhancing angiogenesis. Neoplasia. 2008;10(9):932-9.
  3. Hill R, Bristow RG. The scientific basis of radiotherapy. In: Tannock IF, Hill RP, Bristow RG, Harrington L, editors. The basic science of oncology. 4th ed. Boston: Mc Graw Hill; 2005. p. 298.
  4. Patel SA, Simon MC. Biology of hypoxia-inducible factor-2α in development and disease. Cell Death Differ. 2008;15(4):628-34. http://dx.doi.org/10.1038/cdd.2008.17
  5. Fandrey J, Gorr TA, Gassmann M. Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res. 2006;71(4):642-51. http://dx.doi.org/10.1016/j.cardiores.2006.05.005
  6. Mole DR. Iron homesotasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal. 2010;12(4):445-58. http://dx.doi.org/10.1089/ars.2009.2790
  7. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70(5):1469-80. http://dx.doi.org/10.1124/mol.106.027029
  8. Ardyanto TD, Osaki M, Nagahama Y, Yamaga K, Maeta N, Tamura T, et al. Down-regulation of cobalt-induced HIF-1α expression correlates with cell proliferation and apoptosis in human gastric carcinoma cells. Oncol Report. 2008;19(2):339-43.
  9. N, Triaspolitica. "Kanker Payudara: Informasi, Penyebab, Gejala, Stadium Dan Pengobatan." Mau Nanya Dong Dok. N.p, 28 June 2017. Web. 30 June 2017.<https://nanyadongdok.blogspot.com/2017/06/kanker-payudara-informasi-penyebab.html>.
  10. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000-5. http://dx.doi.org/10.1158/1078-0432.CCR-08-0746
  11. Peng X, Karna P, Cao Z, Jiang B, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and HIF-1 signal pathways increases resistance to apoptosis by upregulating survivin gene expression. J Biol Chem. 2006;281(36):25903-14. http://dx.doi.org/10.1074/jbc.M603414200
  12. Li F and Ling X. Survivin study: an update of 'what is the next wave'? J Cell Physiol. 2006;208(3):476-86. http://dx.doi.org/10.1002/jcp.20634
  13. Maxwell P, Salnikow K. HIF-1: An oxygen and metal responsive transcription factor. Cancer Biol Ther. 2004;3(1):29-35. http://dx.doi.org/10.4161/cbt.3.1.547
  14. Aulia G. Modulasi stress oksidatif pada ketahanan hidup sel punca kanker payudara (CD24-/CD44+) melalui induksi rotenone: tinjauan pada ekspresi manganese superoxide dismutase [tesis]. Jakarta: Universitas Indonesia; 2012. Indonesian.
  15. Hendrawan S, Jusman SWA, Ferdinal F, Prijanti AR, Wanandi SI, Sadikin M. Expression of hypoxia inducible factor-1α (HIF-1α) gene and apoptosis in the heart induced by systemic hypoxia. Med J Indones. 2009;18(2):97-101. http://dx.doi.org/10.13181/mji.v18i2.344
  16. Ardyanto TD, Osaki M, Tokuyasu N, Nagahama Y, Ito H. CoCl2-induced HIF-1α expression correlates with proliferation and apoptosis in MKN-1 cells: A possible role for the PI3K/Akt pathway. Int J Oncol. 2006;29(3):549-55.
  17. Kothari S, Cizeau J, McMillan-Ward E, Israels SJ, Bailes M, Ens K, et al. BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. Oncogene 2003;22(30):4734-44. http://dx.doi.org/10.1038/sj.onc.1206666
  18. Galanis A, Pappa A, Giannakakis A, Lanitis E, Dangaj D, Sandaltzopoulos R. Reactive oxygen species and HIF-1 signalling in cancer. Cancer Lett. 2008;266(1):12-20. http://dx.doi.org/10.1016/j.canlet.2008.02.028
  19. Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res. 2000;6(1):127-34.
  20. Wu XY, Fu ZX, Wang XH. Effect of hypoxia-inducible factor 1-α on Survivin in colorectal cancer. Mol Med Rep. 2010;3(3):409-15.
  21. Kanwar JR, Shen WP, Kanwar RK, Berg RW, Krissansen GW. Effects of survivin antagonists on growth of established tumors and B7-1 immunogene therapy. J Natl Cancer Inst. 2001;93(20):1541-52. http://dx.doi.org/10.1093/jnci/93.20.1541
  22. Brizel DM. Chemical modifiers of radiation response. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 5th ed. Philadelphia: Lippincott-Raven Publisher; 2008. p. 611-19.
  23. Sekarutami SM. Pengaruh hipksia terhadap angiogenesis dan proliferasi sel kanker serviks uteri: hubungannya dengan respon tumor terhadap kombinasi radiasi dengan karbogen-nikotinamdi (KON) sebagai hypoxia modifier [disertasi]. Jakarta: Universitas Indonesia; 2010. Indonesian.

Copyright (c) 2014 Reni Paramita, Mohamad Sadikin, Noorwati Sutandyo, Septelia I. Wanandi

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

All articles and issues in Medical Journal of Indonesia have unique DOI number registered in Crossref.
Unique Visitors